Although extensive research has focused on the etiologic agent in prion disease, infectivity of full length recombinant prion protein (PrP) has not yet been shown, and there is no genetic animal model of a transmissible spongiform encephalopathy (TSE). Based on structural PrP NMR studies of the elk PrP (K. Wuthrich laboratory), we have developed a transgenic mouse model with 2 amino acid differences from wild type PrP leading to a structural alteration in mouse PrP. The transgenic mouse has an extremely well- defined, rigid loop which connects a beta sheet with an alpha helix. Surprisingly, the transgenic mice develop a spontaneous neurologic disease with 100% penetrance characterized by vacuolar change, gliosis, microglial activation, and PrP plaques in the brain, similar to deer with chronic wasting disease (CWD) and patients with variant Creutzfeldt-Jakob disease (vCJD) or Gerstmann-Straussler-Scheinker syndrome (GSS). Our short term goal is to determine whether the newly developed mice with plaques have developed a transmissible prion disease. If infectious, this transgenic mouse would be the first model of an infectious genetically generated TSE from a full length prion protein, and would be particularly intriguing because the exact structural change has already been characterized. In addition, we will elucidate whether this known structural change has altered the species barrier. The hypothesis underlying our proposed research aims is that the "rigid loop" (RL) PrP is a misfolded protein which leads to infectious amyloid plaques and neurodegeneration, similar to a human familial TSE. The goals of the proposed studies are to: (1) determine whether the RL PrP is infectious and how the two mutations alter the species barrier and (2) characterize the neurodegenerative disease caused by the rigid loop and to understand the basis of the neurodegeneration. The studies using the described RL mouse would be the first time a known structural feature of PrP is modeled by transgenesis to study TSE susceptibility and pathogenesis. By elucidating the impact of the RL structure in TSE susceptibility and pathogenesis, we hope to gain basic insights into prion induced neurodegeneration and plaque formation, PrP conversion, and species barriers in prion disease.